Novel Compounds

ABSTRACT

This invention relates to novel phenyl sulfone compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.

This application is a divisional of Application No. 10/547,987, filedSep. 8, 2005, which is a 371 of International Application No.PCT/EP2004/002554,filed Mar. 9, 2004.

This invention relates to novel phenyl sulfone compounds havingpharmacological activity, processes for their preparation, tocompositions containing them and to their use in the treatment of CNSand other disorders.

WO 99/37623 (SmithKline Beecham plc) and EP 930302 (F. Hoffman La Roche)both describe a series of piperazinyl benzenesulfone derivatives whichare claimed to have affinity for the 5-HT₆ receptor. DE 4238994 (BASF)describes a series of benzenesulfone derivatives which are claimed to beuseful as markers for fingerprinting petroleum and petroleum products.EP602523 (Hoechst) describes a series of benzoyl guanidine derivativeswhich are claimed to be useful in a variety of cardiovascular disorders.WO 95/14004 (Pierre Fabre Medicament) describes a series of indolylderivatives which are claimed to have affinity for the 5-HT₁ receptor.

A structurally novel class of compounds has now been found which alsopossess affinity for the 5-HT₆ receptor. The present invention thereforeprovides, in a first aspect, a compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein:

R¹ and R² independently represent hydrogen or C₁₋₆ alkyl or R¹ is linkedto R² to form a group (CH₂)₂, (CH₂)₃ or (CH₂)₄;

R³ independently represents hydrogen, halogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkanoyl, CN, CF₃, OCH₂CF₃, OCF₃, hydroxyC₁₋₆ alkyl,hydroxyC₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkoxyC₁₋₆ alkoxy, nitro,amino, C₁₋₆ alkylamino, diC₁₋₆ alkylamino or NR⁴COR⁵, where R⁴ and R⁵are independently hydrogen or C₁₋₆ alkyl;

m represents an integer from 1 to 5, such that wherein m is an integergreater than 1, said R² groups may optionally be linked to form a groupCH₂, (CH₂)₂ or (CH₂)₃; n represents an integer from 1 to 4;

p represents 1 or 2;

A represents a group —Ar¹ or —Ar²Ar³;

Ar¹ represents unsubstituted phenyl, naphthyl optionally substituted by1, 2 or 3 substituents or monocyclic heteroaryl linked to the SO₂ groupvia a carbon atom and optionally substituted by 1, 2 or 3 substituents;

Ar² represents phenyl or a monocyclic heteroaryl group linked to the SO₂group via a carbon atom, each of which may be optionally substituted by1, 2 or 3 substituents;

Ar³ represents a monocyclic heteroaryl group optionally substituted by1, 2 or 3 substituents;

substituents on Ar¹, Ar² and Ar³ are independently selected from thegroup consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl,trifluoromethoxy, C₁₋₆ alkyl, trifluoromethanesulfonyloxy,pentafluoroethyl, C₁₋₆ alkoxy, arylC₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₆alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl,arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl, C₁₋₆ alkylsulfonamido, C₁₋₆alkylNHCO—, C₁₋₆ alkylCONH—C₁₋₆ alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆alkylNHCOC₁₋₆ alkyl-, C₁₋₆ alkylCONHC₁₋₆ alkyl-, arylsulfonamido,arylCONH—, arylNHCO—, arylsulfonamidoC₁₋₆ alkyl, arylCONHC₁₋₆ alkyl,arylNHCOC₁₋₆ alkyl, aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or agroup CONR⁶R⁷ or SO₂NR⁶R⁷, wherein R⁶ and R⁷ independently representhydrogen or C₁₋₆ alkyl or together may be fused to form a 5- to7-membered aromatic or non-aromatic heterocyclic ring optionallyinterrupted by an O or S atom; or solvates thereof.

In one particular aspect of the present invention, there is provided acompound of formula (I) as defined above wherein p represents 1.

Specific compounds of formula (I) which may be mentioned are thosewherein A represents Ar¹, Ar¹ represents unsubstituted phenyl and R³represents halogen or CF₃.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched and the groups alkoxy and alkanoyl shall beinterpreted similarly. Alkyl moieties are more preferably C₁₋₄ alkyl,eg. methyl or ethyl. The term ‘halogen’ is used herein to describe,unless otherwise stated, a group selected from fluorine, chlorine,bromine or iodine.

The term “aryl” includes phenyl and naphthyl.

The term “monocyclic heteroaryl” is intended to mean a 5-7 memberedmonocyclic aromatic ring containing 1 to 3 heteroatoms selected fromoxygen, nitrogen and sulfur.

Suitable examples of such monocyclic aromatic rings include thienyl,furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl,oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl,pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Heteroaryl groups, asdescribed above, may be linked to the remainder of the molecule via acarbon atom or, when present, a suitable nitrogen atom except whereotherwise indicated above.

It will be appreciated that wherein the above mentioned aryl orheteroaryl groups have more than one substituent, said substituents maybe linked to form a ring, for example a carboxyl and amine group may belinked to form an amide group.

Preferably R¹ represents hydrogen or methyl, most preferably hydrogen.

Preferably R² represents hydrogen or methyl, most preferably hydrogen.

Preferably R³ represents hydrogen or halogen, most preferably hydrogenor a chlorine atom.

Preferably m and n both represent 1.

Preferably p represents 1.

Preferably A represents a group —Ar¹.

When A represents a group —Ar¹, Ar¹ preferably represents unsubstitutedphenyl.

Preferred compounds according to the invention include examples E1-E3 asshown below, or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.The present invention includes within its scope all possiblestoichiometric and non-stoichiometric forms.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be solvated,eg. as the hydrate. This invention includes within its scopestoichiometric solvates (eg. hydrates) as well as compounds containingvariable amounts of solvent (eg. water).

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers) and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

(a) reacting a compound of formula (II)

wherein R³, n and A are as defined above and L¹ represents a suitableleaving group such as a halogen atom (e.g. a chlorine, bromine or iodineatom) or a trifluoromethylsulfonyloxy group, with a compound of formula(III)

wherein R², m and p are as defined above and R^(1a) is as defined for R¹or represents a suitable N-protecting group (such as t-butyloxycarbonyl(Boc), methyl or benzyloxycarbonyl) and thereafter as necessary removingan R^(1a) N-protecting group; or

(b) deprotecting a compound of formula (I) which is protected; andoptionally thereafter

(c) interconversion to other compounds of formula (I).

Process (a) typically comprises the use of a palladium, nickel or coppercatalyst, for example a mixture of a palladium source such as Pd₂(dba)₃and a suitable ligand such as 22,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) or(2-dicyclohexylphosphanylphenyl)-dimethylamine, together with a suitablebase such as sodium t-butoxide or cesium carbonate, in an inert solventsuch as 1,4-dioxane.

In process (b), examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulfonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid) or reductively (e.g.hydrogenolysis of a benzyl group or reductive removal of a2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid) asappropriate. Other suitable amine protecting groups includetrifluoroacetyl (—COCF₃) which may be removed by base catalysedhydrolysis or a solid phase resin bound benzyl group, such as aMerrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), whichmay be removed by acid catalysed hydrolysis, for example withtrifluoroacetic acid. A further amine protecting group includes methylwhich may be removed using standard methods for N-dealkylation (e.g.1-chloroethyl chloroformate under basic conditions followed by treatmentwith methanol).

Process (c) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic or electrophilic aromatic substitution, ester hydrolysis oramide bond formation. For example, N-dealkylation of a compound offormula (I) wherein R¹ represents an alkyl group to give a compound offormula (I) wherein R¹ represents hydrogen. It will be appreciated thatsuch interconversion may be interconversion of protected derivatives offormula (I) which may subsequently be deprotected followinginterconversion.

Compounds of formula (II) may be prepared by reaction of a compound offormula (IV)

wherein R³, n and L¹ are as defined above and L² represents a suitableleaving group such as a halogen atom (e.g. a fluorine or chlorine atom),with a compound of formula A-M wherein A is as defined above and M is ametal residue such as magnesium halide or lithium in a suitable solventsuch as tetrahydrofuran.

Compounds of formula (III) and (IV) are either known in the literatureor can be prepared by known methods.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable saltshave affinity for the 5-HT₆ receptor and are believed to be of potentialuse in the treatment of certain CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorders, migraine,cognitive memory disorders (e.g. Alzheimers disease, age relatedcognitive decline and mild cognitive impairment), Parkinsons Disease,ADHD (Attention Deficit Disorder/Hyperactivity Syndrome), sleepdisorders (including disturbances of Circadian rhythm), feedingdisorders such as anorexia and bulimia, panic attacks, withdrawal fromdrug abuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia (in particular cognitive deficits of schizophrenia),stroke and also disorders associated with spinal trauma and/or headinjury such as hydrocephalus. Compounds of the invention are alsoexpected to be of use in the treatment of certain GI (gastrointestinal)disorders such as IBS (Irritable Bowel Syndrome). Compounds of theinvention are also expected to be of use in the treatment of obesity.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of the abovedisorders. In particular the invention provides for a compound offormula (I) or a pharmaceutically acceptable salt thereof, for use inthe treatment of depression, anxiety, Alzheimers disease, age relatedcognitive decline, ADHD, obesity, mild cognitive impairment,schizophrenia, cognitive deficits in schizophrenia and stroke.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

5-HT₆ antagonists have the potential to be capable of increasing basaland learning-induced polysialylated neuron cell frequency in brainregions such as the rat medial temporal lobe and associated hippocampus,as described in WO 03/066056. Thus, according to a further aspect of thepresent invention, we provide a method of promoting neuronal growthwithin the central nervous system of a mammal which comprises the stepof administering a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment or prophylaxis ofthe above disorders.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. The present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 200 mg, for example 20 to 40 mg; and such unitdoses will preferably be administered once a day, althoughadministration more than once a day may be required; and such therapymay extend for a number of weeks or months.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

DESCRIPTION 1 3-Bromophenylsulfonyl Fluoride (D1)

To a stirred solution of 3-bromophenylsulfonyl chloride (5 g, 0.0196mol) in acetonitrile (20 ml) was added potassium fluoride (2.27 g,0.0391 mol) followed by 18-crown-6 ether (0.08 g) and the reactionstirred at room temperature for 18 h. The reaction mixture was thenwashed with water (60 ml), extracted with ethyl acetate (3×80 ml) andthe combined organic extracts dried (Na₂SO₄). Solvents were evaporatedin vacuo to give a yellow oil (3.79 g, 81%).

¹H NMR (CDCl₃):δ 7.55 (1H, t), 7.92 (1H, d), 7.95 (1H, d), 8.14 (1H, s).

DESCRIPTION 2 3-Phenylsulfonylbromobenzene (D2)

To a stirred solution of 3-bromophenylsulfonyl fluoride (D1) (1 g, 4.18mmol) in dry THF (20 ml) at −78° C., under argon was addedphenylmagnesium bromide (1 M, 1.4 ml, 4.18 mmol) dropwise. The reactionwas left to warm to room temperature overnight and then quenched withammonium chloride (50 ml), extracted with ethyl acetate (3×40 ml) andthe combined organic extracts dried (Na₂SO₄). Solvents were evaporatedin vacuo to give a colourless solid (1.09 g, 88%).

¹H NMR (CDCl₃): δ 7.40 (1H, t), 7.50-7.55 (2H, m), 7.60 (1H, d), 7.69(1H, d), 7.86 (1H, d), 7.93 (2H, d), 8.08 (1H, s).

DESCRIPTION 31-(3-Phenylsulfonylphenyl)-4-tert-butyloxycarbonylpiperazine (D3)

A solution of 2 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (62mg, 0.1 mmol) and cesium carbonate (329 mg, 1.01 mmol) in dry dioxane (2ml) were sonicated for 45 min, under argon. To this solution was added3-phenylsulfonylbromobenzene (D2) (200 mg, 0.67 mmol) and1-(tert-butyloxycarbonyl)piperazine (314 mg, 1.68 mmol) and the reactionheated at 100° C. for 18 h. The reaction mixture was evaporated in vacuoand the residue partitioned between water (50 ml) and dichloromethane(50 ml). The organic layer was washed with sat. sodium hydrogencarbonate (50 ml), 10% citric acid (50 ml), brine (50 ml) and then dried(MgSO₄). Solvents evaporated in vacuo and the residue purified by columnchromatography (silica gel; 0-60% ethyl acetate/petroleum ether) to givethe product as a colourless oil (192 mg, 71%)

¹H NMR (CDCl₃): δ 1.48 (9H, s), 3.15-3.20 (4H, t), 3.55-3.60 (4H, t),7.05 (1H, m), 7.36 (2H, m), 7.45 (1H, m), 7.50 (2H, m), 7.56 (1H, m),7.94 (2H, d).

Mass Spectrum: C₂₁H₂₆N₂SO₄ requires 402; found: 403 (MH⁺).

DESCRIPTION 4 4-(3-Phenylsulfonyl-2-chlorophenyl)piperazine-1-carboxylicacid tert-butyl ester (D4A) and4-(5-Phenylsulfonyl-2-chlorophenyl)piperazine-1-carboxylic acidtert-butyl ester (D4B)

1-(3-Phenylsulfonylphenyl)-4-tert-butyloxycarbonyl piperazine (D3) (84mg, 0.20 mmol) was dissolved in acetic acid (5 ml) and heated at 60° C.Then N-chlorosuccinimide (28 mg, 0.20 mmol) was added and the stirredreaction mixture was heated at 60° C. for 24 h, then cooled to ambienttemperature. The reaction mixture was diluted in dichloromethane andneutralised by addition of an aqueous solution of NaHCO₃. The organiclayer was dried with MgSO₄ and evaporated in vacuo to give two mainproducts, which were separated by column chromatography eluting withdichloromethane/ethyl acetate (0-30%).

Product D4A: 18 mg.

¹H-NMR (CDCl₃): δ 1.46 (9H, s), 2.92 (4H, t), 3.53 (4H, t), 7.26 (1 H,dd), 7.44 (1H, t), 7.50 (2H, tt), 7.59 (1H, tt), 7.94 (2H, dd), 8.10(1H, dd).

Mass Spectrum: C₂₁H₂₅ ³⁵ClN₂O₄S requires 436; Found 437 (MH⁺).

Product D4B: 40 mg.

¹H-NMR (CDCl₃): δ 1.49 (9H, s), 3.01 (4H, t), 3.59 (4H, t), 7.47 (1H,d), 7.49-7.54 (3H, m), 7.55 (1H, d), 7.58 (1H, tt), 7.92 (2H, m).

Mass Spectrum: C₂₁H₂₅ ³⁵ClN₂O₄S requires 436; Found 437 (MH⁺).

EXAMPLE 1 1-(3-Phenylsulfonyl-phenyl)piperazine (E1)

A solution of 1-(3-phenylsulfonylphenyl)-4-tert-butyloxycarbonylpiperazine (D3) (96 mg, 0.23 mmol) in 1,4-dioxane (3 ml) and 4M HCl (3ml) was refluxed at 60° C. for 1 h. The solvents were then evaporated invacuo and the product dried under high vacuum to give a yellow solid (69mg, 96%)

¹H NMR (DMSO-d₆): δ 1.49 (9H, s), 3.21 (4H, m), 3.44-3.47 (4H, m), 7.26(1H, d), 7.37 (1H, d), 7.45-7.50 (2H, m), 7.60-7.65 (2H, m), 7.65-7.70(1H, m), 7.95-7.98 (2H, d), 9.15 (2H, br-s).

Mass Spectrum: C₁₆H₁₈N₂SO₂ requires 302; found: 303 (MH⁺).

EXAMPLE 2 1-(3-Phenylsulfonyl-2-chlorophenyl)piperazine (E2)

4-(3-Phenylsulfonyl-2-chlorophenyl)piperazine-1 -carboxylic acidtert-butyl ester (D4A) was dissolved in 8 ml of 1,4-dioxane/4 M HCl 1:1.The mixture was heated at 60° C. for 1 h. The solvent was evaporated invacuo to give the title product as a colourless solid.

¹H-NMR (CD₃OD): 3.21-3.35 (8 H, m), 7.53-7.69 (5H, m), 7.90 (2H, d),8.14 (1H, d),

Mass Spectrum: C₁₆H₁₇ ³⁵ClN₂O₂S requires 336; Found 337 (MH⁺).

EXAMPLE 3 1-(5-Phenylsulfonyl-2-chlorophenyl)piperazine (E3)

4-(5-Phenylsulfonyl-2-chlorophenyl)piperazine-1 -carboxylic acidtert-butyl ester (D4B) was dissolved in 8 ml of 1,4-dioxane/4 M HCl 1:1.The mixture was heated at 60° C. for 1 h. The solvent was evaporated invacuo to give the title product as a colourless solid.

¹H-NMR (CD₃OD): 3.29-3.59 (8 H, m), 7.57-7.70 (6H, m), 7.97 (2H, d).

Mass Spectrum: C₁₆H₁₇ ³⁵ClN₂O₂S requires 336; Found 337 (MH⁺).

Pharmacological Data

Compounds can be tested following the procedures outlined in WO98/27081.The compounds of Examples E1-E3 were tested and showed good affinity forthe 5-HT₆ receptor, having pKi values >7.5 at human cloned 5-HT₆receptors, in particular the compounds of Examples E1-E2 had pKi values>8.0.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein: R¹ and R² independently represent hydrogen or C₁₋₆ alkyl or R¹is linked to R² to form a group (CH₂)₂, (CH₂)₃ or (CH₂)₄; R³independently represents hydrogen, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkanoyl, CN, CF₃, OCH₂CF₃, OCF₃, hydroxyC₁₋₆ alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkoxyC₁₋₆ alkoxy, nitro, amino, C₁₋₆alkylamino, diC₁₋₆ alkylamino or NR⁴COR⁵, where R⁴ and R⁵ areindependently hydrogen or C₁₋₆ alkyl; m represents an integer from 1 to5, such that wherein m is an integer greater than 1, said R² groups mayoptionally be linked to form a group CH₂, (CH₂)₂ or (CH₂)₃; n representsan integer from 1 to 4; p represents 1 or 2; A represents a group −Ar¹or −Ar²Ar³; Ar¹ represents naphthyl optionally substituted by 1, 2 or 3substituents or monocyclic heteroaryl linked to the SO₂ group via acarbon atom and optionally substituted by 1, 2 or 3 substituents; Ar²represents phenyl or a monocyclic heteroaryl group linked to the SO₂group via a carbon atom, each of which may be optionally substituted by1, 2 or 3 substituents; Ar³ represents a monocyclic heteroaryl groupoptionally substituted by 1, 2 or 3 substituents; substituents on Ar¹,Ar² and Ar³ are independently selected from the group consisting ofhalogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, C₁₋₆ alkoxy,arylC₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆alkylsulfonylC₁₋₆ alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆alkyl, C₁₋₆ alkylsulfonamido, C₁₋₆ alkylNHCO—, C₁₋₆ alkylCONH—C₁₋₆alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylNHCOC₁₋₆ alkyl-, C₁₋₆alkylCONHC₁₋₆ alkyl-, arylsulfonamido, arylCONH—, aryINHCO—,arylsulfonamidoC₁₋₆ alkyl, arylCONHC₁₋₆ alkyl, arylNHCOC₁₋₆ alkyl,aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or a group CONR⁶R⁷ orSO₂NR⁶R⁷, wherein R⁶ and R⁷ independently represent hydrogen or C₁₋₆alkyl or together may be fused to form a 5- to 7-membered aromatic ornon-aromatic heterocyclic ring optionally interrupted by an O or S atom.2. A pharmaceutical composition which comprises the compound accordingto claim 1 and a pharmaceutically acceptable carrier or excipient.
 3. Amethod of treating depression, anxiety, obesity, mild cognitiveimpairment, and schizophrenia, which comprises administering atherapeutically effective amount of the compound according to claim 1 ora pharmaceutically acceptable salt thereof to a patient in need thereof.